The present invention relates to a series of new compounds, to which we have assigned the class name "Phomactin". These compounds may be produced by cultivation of an appropriate microorganism (fungus) of the genus Phoma. The invention also provides a fermentation process for producing these compounds using a novel strain of microorganism of the genus Phoma, as well as the new strain itself, and provides methods and compositions using the new compounds of the invention as platelet activating factor antagonists.
"Platelet activating factor" is herein abbreviated, as is conventional, to "PAF".
Natureal PAF, at least as isolated from mammalian tissues, is a mixture of from 2 to 5 phospholipids, the number depending upon the nature of the original tissue. The major constituents of PAF may be represented by the formula (A): ##STR1## in which R represents a long chain aliphatic hydrocarbon group, which may be saturated or unsaturated. Natural PAF is levorotatory and the various components of natural PAF may be identified, for example as: l-C.sub.16:0 =formula (A) where R represents a hexadecyl group; l-C.sub.18:0 =formula (A) where R represents an octadecyl group; or l-C.sub.18:1 =formula (A) where R represents a 9(Z)-octadecenyl group. The convention used above for identifying the constituents of PAF gives the rotation first (l. in the above examples), followed by the number of carbon atoms, and finally the number of double bonds.
PAF exhibits a strong platelet activating and aggregating effect, from which it derives its name. It has, however, in recent years been seen to be a potentially crucial mediator in a wide variety of pathological processes. Thus, it also has a hypotensive effect and increases vasopermeability; it is believed to be an active agent in the induction of the shock state (for example endotoxin-induced shock) and to act as a mediator of inflammatory disease. It has also been found to play a role in cardiac and systemic anaphylaxis, gastric and intestinal ulceration, psoriasis and immune and renal disorders.
It is not, therefore, surprising that, as a result, PAF antagonists have been investigated with a view to developing new types of treatment for the above pathologies, and notably new types of anti-shock agent and anti-inflammatory agent. Accordingly, various compounds have been investigated in an attempt to find such PAF antagonists, and, currently, several compounds are known as PAF antagonists. Although the chemical structure of known PAF antagonists varies widely, and there appears to be no obvious common factor linking their chemical structures, in general, known materials having PAF-antagonist activity may be classified according to their chemical structure as either PAF type or non-PAF type compounds. Of the known compounds, PAF type antagonists are mostly prepared by chemical synthesis, whilst non-PAF type antagonists are mostly recovered from the secondary metabolites of plants and microorganisms. Examples of compounds of the non-PAF type include, for example, ginkgolide (isolated from Ginkgo biloba), kadzurenone (isolated from Piper futokadzura), veraguensin (isolated from Magnolia acuminata), galbengin and galbrabin (isolated from Himantandra velgravena), nectandrin A and B (isolated from Nectandra rigida). burseran (isolated from Bursera microphylla) [details of the above compounds are given by P. Braquet and J. J. Godfroid: Trends in Pharm. Sci., Vol. 7, pp. 397 et seq (1986)], a gliotoxin derivative [isolated from Penicillium terlikowskii: M. Okamoto, Chem. Pharm. Bull., 34, 340 (1986)] and a diketopiperazine derivative [isolated from Streptomyces sp.: S. Takase, J. Org. Chem., 52, 3485 (1987)].
A variety of PAF-type compounds are known, but these are not relevant to the present invention.
A review of the nature and uses of PAF antagonists is given by P. Braquet et al., Trends in Pharm. Sci., Vol. 10, pp. 23 et seq (1989), the disclosure of which is incorporated by reference.
We have now discovered a series of new PAF-antagonist compounds of the non-PAF type, which we have, in accordance with current convention, named "the phomactins", and which can be produced by the cultivation of a microorganism, which we have identified as SANK 11486, which belongs to the species Phoma and which has been isolated from the shells of certain crabs.